Drug delivery system for accelerated subcutaneous absorption

ABSTRACT

A method for accelerating subcutaneous absorption of a fluid or drug into the systemic circulation of a specific targeted tissue. A first drug operative to produce local capillary vasodilatation and/or increase the rate of bulk flow of solution through the interstitial space is mixed with a fluid. The fluid may contain a crystalloid solution or a dilute solution of a pharmacologic drug required for a routine or emergency therapeutic treatment for a patient. The first drug is substantially non-toxic to the patient. The fluid mixed with the first drug is then delivered subcutaneously or into deeper tissues of the patient, by use of a hyperdermic needle or infiltration cannula. As the capillaries are dilated, the fluid is efficiently absorbed and circulated systemically.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 10/877,337, filed Jun. 25, 2004, now U.S. Pat. No.7,572,613.

The subject application is related to Applicant's pending U.S. patentapplication Ser. No. 10/877,566, filed Jun. 25, 2004 entitledINFILTRATION CANNULA, the disclosure of which is expressly incorporatedherein by reference.

STATEMENT RE: FEDERALLY SPONSORED RESEARCH/DEVELOPMENT

Not Applicable

BACKGROUND OF THE INVENTION

The present invention relates in general to accelerated subcutaneousabsorption, and more particularly, to a method that accelerates drugabsorption rates with minimal toxicity.

By way of background and to better facilitate a complete understandingof the present invention the following terms shall have the followingdefinitions:

Solvent: A substance (usually a liquid) having the power to dissolveother substances. In the present application, both water andcommercially available crystalloids (e.g. 0.9% sodiumchloride/physiologic saline or lactated Ringer's solution) areconsidered to be exemplary solvents.

Solute: The dissolved substance, the substance dissolved by the solventin a solution. In the present application, preferable solutes includepharmaceutical drugs such as methyl nicotinamide, hyaluronidase,lidocaine, and epinephrine, that are dissolved in a crystalloid solvent.

Solution: The action of changing from a solid or gaseous state to aliquid state, the state of being desolved.

Tumescent Technique or Tumescent Infiltration are defined as a method ofsubcutaneous drug delivery of large volumes of very dilute medicationtogether with dilute epinephrine in isotonic solution of crystalloid(e.g., physiologic saline, lactated Ringer's solution, Hartman'ssolutions, etc.) infiltrated directly into subcutaneous fat or muscle oralong the exterior length of a vein to produce swelling and firmness, ortumescence, of the targeted tissues, and thus produce very slow systemicabsorption as a result of intense subcutaneous vasoconstriction, as wellas direct hydrostatic compression of capillaries and veins. TumescentDrug Delivery, or Tumescent Delivery are synonyms that refer to thetumescent technique for delivering a drug into the subcutaneous space.In other words, tumescent delivery is a process of infiltration of verylarge volumes of very dilute solutions of therapeutic substancesdissolved in a crystalloid solution into subcutaneous tissue to thepoint of producing tumescence of the targeted tissue. Drugs other thanlidocaine can be administered by means of tumescent delivery, that is,by subcutaneous infiltration of extremely dilute drug, with or without avasoconstrictor such as epinephrine.

Tumescent and tumescence are synonyms for swollen and firm.

Tumescent liposuchtion is defined as liposuction performed totally bylocal anesthesia using tumescent local anesthesia.

Tumescent fluid and/or tumescent solution are defined as dilutesolutions of therapeutic substances dissolved in a crystalloid solutionintended for tumescent delivery into subcutaneous tissue.

Tumescent “drug”: the “drug” in the context as an ingredient in atumescent solution and its pharmacokinetic behavior as a result of thepharmacokinetics of a tumescent solution; for example tumescentlidocaine, tumescent epinephrine, tumescent antiobiotic.

Tumescent Local Anesthesia (TLA) is local anesthesia produced by directinfiltrations into subcutaneous tissues of large volumes of very dilutelidocaine (e.g., less than or equal to 1 gram/liter) and epinephrine(e.g., less than or equal to 1 milligram/liter) with sodium bicarbonate(e.g., 10 milliequivalents/liter) in a crystalloid solution such asphysiologic saline (NaCl) or lactated Ringer's solution. Although higherconcentrations can be used and still qualify as TLA, it is generallysafer to use the least (lowest) effective concentration.

Tumescent Local Anesthetic Solution (TLA Solution) is the localanesthetic solution used to produce TLA. Typically, a TLA Solutionconsists of a 10 to 20 fold dilution of commercially availableconcentration of lidocaine and epinephrine. Thus, a commercial solutionof lidocaine and epinephrine contains 10 grams of lidocaine per liter(10 gm/L) and 10 milligrams of epinephrine per liter. In contrast TLASolution typically contains very dilute lidocaine (≦1 gram/liter) andepinephrine (≦1 milligram/liter) with sodium biocarbonate (10milliequivalents/liter) in a crystalloid solution such as physiologicsaline or lactated Ringer's solution. Typically the volume ofinfiltrated TLA Solution is so large that the skin and subcutaneoustissue becomes tumescent, in other words swollen and firm.

Tumescent Pharmacokinetics is defined as the absorption pharmacokinetics[the pharmacologic and physiologic factors associated with the systemicabsorption of a drug] after tumescent infiltration of a drug isdramatically slower than the rate of systemic absorption of routineinjection of the drug. The intense vasoconstriction induced byepinephrine, slows the rate of drug absorption into the centralcirculation and prolongs the local effects of the drug. For example, theduration of local anesthesia with lidocaine is typically 2 hours, incontrast the duration of local anesthesia with tumescent localanesthesia is 12 to 18 hours or more. A similar prolonged effect oftumescent antibiotic infiltration significantly improves theprophylactic effect of preoperative antibiotic therapy in the preventionof surgical site infections.

Bulk flow: The physical flow of a volume of fluid through a space, forexample, water flowing through a sieve or strainer. Water flowingthrough the interstitial space between cells of a tissue is one exampleof the phenomenon of bulk flow in physiology.

In clinical situations such as severe trauma, hypoglycemia ordehydration which requires an immediate systemic administration offluids or drugs, the most effective mode of delivery is often anintravenous (IV) infusion. However, IV infusion is not always easilyaccomplished or possible, in particular when the veins of a patient aredifficult to locate due to severe dehydration or when ambient light isso low that the veins of the patient are not visible. Further,substantial clinical skills are typically required for gaining IVaccess. Therefore, during an emergency situation in isolated areas farfrom trained medical clinicians, IV administration of drugs may not bepossible. As such, often times patients must wait until trainedclinicians and proper facilities are available to insert and establishsecure IV access. However any significant delay in establishing an IVsite and administrating required drugs can have serious adverseconsequences. Thus, there exists a substantial need in the art for asimple, safe technique that can be performed by a layman and whichproduces a rapid systemic administration of a drug or a fluid applied toa patient by subcutaneous infiltration or topical application.

Although not by way of limitation, the present invention is specificallysuited for use with Applicant's Infiltration Cannula disclosed inpending U.S. patent application Ser. No. 10/877,566, filed Jun. 25, 2004entitled INFILTRATION CANNULA, the disclosure of which is expresslyincorporated herein by reference as disclosed therein A suitableInfiltration Cannula consists of a flexible plastic cannula(approximately 15 to 20 cm long) with holes (apertures) arranged alongthe distal 90% of the flexible cannula, and through which tumescentfluid can be rapidly delivered to subcutaneous tissue or muscle. Knownas Kleinfiltrator™ cannulas, these flexible infiltration cannulasprovide a means for relatively rapid fluid resuscitation in emergencysituations when establishing an intravenous (IV) access is not feasible.These flexible infiltration cannulas have important applications intreating wounded soldiers in night-time combat conditions whenestablishing an IV access in total darkness is nearly impossible withoutusing a flash light, and using a flash light might attract deadly enemyfire. Such flexible infiltration cannulas also have importantapplications in treating mass-casualty victims suffering hypovolemia asa result of epidemic infections, biologic warfare, or trauma such asexplosions, burns, radiation exposure, or earthquake associated injury.Such flexible infiltration cannulas also have applications in surgicalpatients wherein the surgeon can provide localized preoperativepreemptive analgesia and simultaneously provide tumescent delivery of aprophylactic dose of an antibiotic aimed precisely at tissues targetedfor surgical intervention.

The present invention comprises a method of accelerated subcutaneousabsorption, which is intended to act in concert with such flexibleinfiltration cannula or other suitable infiltration cannula. Suchinfiltration cannulas allow rapid tumescent infiltration of a largevolume of crystaloid solution (possibly containing additionaltherapeutic drugs) into subcutaneous tissue or muscle. The method ofaccelerated systemic absorption of fluid then provides a means ofmaximizing the delivery of the tumescent solution to the systemiccirculation.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a drug delivery system and method foraccelerating subcutaneous absorption of a fluid or drug. The methodcomprises the use of a first drug, operative to produce local capillaryvasodilatation and/or augmented rate of bulk flow, which is mixed with afluid. The fluid may include a specific crystalloid solution or a dilutesolution of a pharmacologic drug required under a clinical emergency ofa patient. The first drug is substantially non-toxic to the patient. Thefluid mixed with the first drug is then subcutaneously delivered to thepatient. By way of example and not limitation, suitable examples of thefirst drug include methyl-nicotinamide, methyl-nicotinate orhyaluronidase. Exemplary fluids include physiologic saline, lactatedRinger's solution or a dilute solution of pharmacologic drug such as anantibiotic.

Preferably, the fluid mixed with the first drug is delivered to thepatient by subcutaneous infiltration. The subcutaneous infiltration canbe performed by inserting an infiltration cannula under the skin of thepatient, followed by infiltrating the fluid mixed with the first druginto subcutaneous tissue of the patient through the infiltrationcannula. Preferably but optionally, a plastic Kleinfiltrator™ cannula isused as the infiltration cannula, such that a layman can easily performthe infiltration of the fluid.

In the first preferred embodiment of the present invention, a first drugis added a tumescent solution which produces an augmented rate ofsystemic absorption of the solvent (physiologic 0.9% sodium chloride orlactated Ringer's solution) and/or an additional second therapeutic drug(such as an antibiotic) also contained in the solution, when thetumescent solution is injected into the subcutaneous tissue or muscle.The first drug can act to produce either an increased degree ofcapillary vasodilation (for example methylnicotinc acid or nicotinamide)and thereby increase the rate of diffusion of the solvent and/or secondtherapeutic drug across the capillary wall and into the systemiccirculation, or the first drug can act as an agent to increase the rateof bulk flow of fluid through the interstitial gel substance (forexample hyaluronidase) and thereby hasten the spread of the tumescentfluid throughout a larger volume of tissue and thus accelerate systemicabsorption.

In a second embodiment of this invention, two separate solutions oftumescent fluid are injected into the subcutaneous tissue at differentdepths permitting a clinician to preferentially cause a first drug toselectively flow toward and be absorbed into a specific subcutaneoustissue or cutaneous tissue.

For example, a first solution containing a vasoconstrictive drug (suchas epinephrine or vasopressin) may be injected into a relatively deepplane of the subcutaneous tissue. Then a second solution containing atherapeutic drug is injected into a more superficial subcutaneous plane.Thus, the first vasoconstrictive tumescent fluid acts as an agent toprovide a buffer that prevents or delays absorption of the second druginto deeper tissues of the patient. Alternatively, the vasoconstrictivesolution is injected first into the subcutaneous tissue immediatelysubjacent to the skin, and then the second solution containing thetherapeutic drug is injected into a deeper subcutaneous plane. Thereby,a buffer is provided to prevent or delay absorption of the second druginto the superficial subcutaneous tissue or skin of the patient.

The second embodiment of the present invention further comprises amethod of increasing the absorption rate of a therapeutic drug, in whicha first solution is applied in a first level under skin of a patient,and a second solution is applied to a second level under skin of thepatient. The first solution preferably contains the therapeutic drug fortreating the skin of the patient, and the second solution preferablycontains a vasoconstrictive drug only. The second level is deeper thanthe first level to serve as a buffer for preventing or delayingabsorption of the therapeutic drug into deep vascular tissue.Preferably, the first solution further contains a vasodilation drug, andthe vasoconstrictive drug includes epinephrine or vasopressin.

As is well known, in the original version of the tumescent technique,invented by the subject applicant Jeffrey A. Klein, M.D., epinephrinewas added to physiologic saline in order to delay the systemicabsorption of the physiologic saline and a second solute, lidocaine. Thevasoconstriction provided by dilute epinephrine produced both profoundsurgical hemostasis and significantly delayed lidocaine absorption towhich prolong local anesthesia. By combining lidocaine and epinephrinein physiologic saline, the subject applicant facilitated liposuctionprocedures to be accomplished totally by local anesthesia, thus avoidingthe risk of general anesthesia. Such tumescent technique has now becomethe world wide standard of liposuction procedures.

In contrast, in the present invention, the solute(s) in the tumescentsolution are intended to maximize the rate of absorption rather thanminimize the same. There are several preferred drugs and clinical meansfor accelerating the rate of systemic absorption of the tumescentsolution. First, the vasodilators methyl nicotinamide, niacin andlidocaine dilate capillaries and thus may act to increase local tissueblood flow and thereby increase the rate of systemic absorption. Second,hyaluronidase is any one of the class of enzymes that may catalyze thedepolymerization of hyaluronic acid, thereby reducing the viscosity andrendering tissue containing it more permeable. Third, the tumescenttechnique, by virtue of the increased interstitial pressure produced bythe forcibly injecting a large volume of fluid into the subcutaneousspace will accelerate the systemic absorption of the fluid (solvent) andany drugs (solutes) contained therein. Fourth, by heating the tumescentfluid to body temperature, one can avoid vasoconstriction that mightresult from using a cooler fluid.

BRIEF DESCRIPTION OF THE DRAWINGS

These, as well as other features of the present invention, will becomeapparent upon reference to the drawings wherein:

FIG. 1 shows a flow chart of an accelerated subcutaneous absorptionprovided by the present invention; and

FIG. 2 shows a flow chart of a tumescent technique for increasingsubcutaneous absorption rate into specifically targeted tissues, bycombining applications of both vasodilator and vasoconstrictivetumescent solution.

DETAILED DESCRIPTION OF THE INVENTION

Referring now to the drawings wherein the showings are for purpose ofillustrating preferred embodiments of the present invention only, andnot for purposes of limiting the same, FIG. 1, illustrates the method ofthe present invention for accelerating subcutaneous absorption. Suchmethod can be applied in various clinical conditions under whichaccelerated systemic or topical delivery of a specific fluid or drug isrequired. In addition, the method provided by the present invention canbe easily performed by a layman in locations remote from specialized ortechnically demanding medical equipment without the requirement ofspecial clinical skills. In step 101, a drug that is operative to causecapillary vasodilatation or vasodilatation of subcutaneous blood vesselsis mixed with a fluid or a solution of a pharmacologic drug required bythe patient.

The fluid or the solution of pharmacologic drug may include acrystalloid solution or a dilute solution of pharmacologic drug such asan antibiotic. The drug used to accelerate the absorption rate of thefluid or the pharmacologic drug is operative to cause capillaryvasodilatation, that is, vasodilatation of cutaneous blood vessels. Thedilation of capillaries increases the rate of blood flowing through theaffected subcutaneous tissue; and consequently, increases the rate ofabsorption into the systemic circulation of the fluid or pharmacologicdrug. As the rate of absorption and circulation of the fluid orpharmacologic drug increases, a clinically significant degree ofsystemic absorption of the fluid or pharmacologic drug can be achievedwithout the application of IV access. Currently, many drugs areavailable to provide the vasodilatation of cutaneous blood vessels of ahuman body. However, it is appreciated that those drugs which arepharmacologic and potentially toxic to the human bodies are not theappropriate candidates for such drug. For example, although lidocaine iseffective to cause dilation of capillaries and increase the rate ofblood flowing through affected subcutaneous tissue, which in turnaccelerates the absorption rate of drug, it might not be an appropriatecandidate for such a drug due to its potentially toxic effect if itsconcentration is too high. In the preferred embodiment, empirical datashows that topical application of aqueous solution ofmethyl-nicotinamide or methyl-nicotinate (methyl-nicotinic acid)introduces a very obvious erythema of the affected area of the patientwithin minutes. As dilute methyl-nicotinamide or methyl-nicotinate doesnot provide significant toxic effect to the human body, it can thus beused as the drug for accelerating the absorption rate of thepharmacologic drug. It will be appreciated that methyl-nicotinamied ormethyl-nicotinate increases local tissue blood flow, but is not the onlydrug suitable for use in acceleration of systemic absorption. Otherdrugs that accelerate systemic absorption by other effects can also beused. For example, an enzyme such as hyaluronidase catalyzesdepolymerization of hyaluronic acid and thereby reduces the viscosity ofthe interstitial gel substance and renders the tissue containing it morepermeable. Therefore, the rate of systemic absorption can be increasedby adding hyaluronidase to the tumescent solution.

In step 103, an infiltration cannula is inserted under the skin of thepatient. Although all conventional infiltration cannulas arecontemplated herein, preferably, a flexible infiltration cannula is usedand inserted into the skin to approach the subcutaneous tissue to betreated. Examples of both rigid and flexible suitable cannulas aredisclosed in Applicant's pending U.S. patent application Ser. No.10/442,370, entitled “Infiltration Cannula” filed May 21, 2003, andpending application entitled “Infiltration Cannula” Ser. No. 10/877,566,filed June 25, the disclosures of which are expressly incorporatedherein by reference. In step 105, the fluid or dilute solution ofpharmacologic drug mixed with the drug for accelerating the absorptionof the pharmacologic drug is injected or infiltrated into the desiredsubcutaneous tissue under the skin via the infiltration cannula.Therefore, the fluid or dilute solution can be efficiently absorbed bythe subcutaneous tissue and delivered to the desired area of thepatient.

Under certain clinical conditions, the tumescent technique foraccelerating absorption rate can be performed by applications of bothvasodilator and vasoconstrictive tumescent solutions in order to directa drug toward a targeted tissue such as axillary skin and away fromother tissues such as systemic circulation. As shown in FIG. 3, when theskin of a patient is to be treated, a vasoconstrictive tumescentsolution containing epinephrine (with or without local anesthesia) maybe infiltrated in the deep plane of the subcutaneous tissue of thepatient in step 301. A therapeutic tumescent solution of a drug fortreating the skin is then infiltrated in the superficial plane locatedabove the deep plane in step 303. By the infiltration of thevasoconsctrictive tumescent solution, the deep plane of tumescentsubcutaneous tissue acts as a buffer or barricade that prevents ordelays absorption of the drug into deeper highly vascular tissue. When alarge area of the skin is to be treated, or when acceleration of thedrug absorption rate is required, the therapeutic tumescent solutiondrug is mixed with a vasodialator drug or a drug increasing bulk flow ofthe drug as mentioned above in step 302. Alternatively, for thetreatments of deep tissues, organs and internal viscera, avasoconstrictive tumescent solution is applied superficially orperipherally relative to the tissue or organ, while the therapeutictumescent solution containing a drug for treating the deep tissues isapplied deeply or adjacent to or into the tissue or organ. Again, when alarge area of deep tissues is to be treated, a drug for increasingabsorption rate of the drug is mixed with the therapeutic tumescentsolution.

The scope of this disclosure is not limited by these exemplaryembodiments. Numerous variations, whether explicitly provided for by thespecification or implied by the specification, such as variations inshape, structure, dimension, type of material or manufacturing processmay be implemented by one of skill in the art in view of thisdisclosure.

1. A method of increasing absorption rate of a therapeutic drug,comprising: applying a first solution in a first level under skin of apatient, wherein the first solution contains a therapeutic drug fortreating subcutaneous tissue of the patient; and applying a secondsolution in a second level under the skin of the patient, wherein thesecond solution contains a vasoconstrictive drug; wherein the secondlevel is deeper than the first level to serve as a buffer for preventingor delaying absorption of the therapeutic drug into deep vasculartissue.
 2. The method of claim 1, wherein the first solution furthercontains a vasodilation drug.
 3. The method of claim 1, wherein thevasoconstrictive drug includes epinephrine.
 4. The method of claim 1,wherein the first level includes a deep plane of the subcutaneoustissue, and the second level includes a superficial plane immediatelybelow dermis of the patient.
 5. A method of increasing absorption rateof a therapeutic drug, comprising: applying a first solution in a firstlevel under the skin of a patient, wherein the first solution contains atherapeutic drug for treating the skin of the patient; and applying asecond solution in a second level under the skin of the patient, whereinthe second solution contains a vasoconstrictive drug only; wherein thefirst level is deeper than the second level to serve as a buffer forpreventing or delaying absorption of the therapeutic drug intosuperficial region of the skin.
 6. The method of claim 5, wherein thefirst solution further contains a vasodilation drug.
 7. The method ofclaim 6, wherein the vasoconstrictive drug comprises epinephrine.